Urothelial cancer (UC) or bladder cancer is a leading cause of death worldwide. Most of the patients who present with superficial UC tumours will experience a recurrence within 5 years and almost 90% of these patients will have a recurrence within 15 years.
Haematuria, which refers to the presence of blood in urine, is a presenting symptom for a variety of diseases, including UC. The number of patients presenting with haematuria is progressively increasing in our aging population and the diagnosis of serious diseases in some of these patients can be delayed when triage is ineffective. Therefore new risk stratification approaches are needed.
Diagnosis of the underlying cause of hematuria is a significant healthcare challenge. Hematuria can indicate the presence of UC, but it is also a symptom of a wide range of other pathologies including urolithiasis, benign prostate enlargement (BPE), renal disease and other urinary tract cancers. The final diagnosis for haematuria patients ranges from no diagnosis, through benign conditions including urinary infection, stone disease, BPE to renal diseases and malignant causes. UC is the most common malignancy in haematuric patients and is the fourth most common cancer in men. UC was the estimated cause of death in 150,200 people, worldwide in 2008.
UC is associated with many risk factors, for example its development is three times more common in men than in women. However, this gender disparity is largely historical and is related to smoking habits. Smoking increases the risk of UC four-fold and cessation of smoking is associated with a decreased risk. Although UC is associated with smoking and carcinogen exposure, urothelial cancers that arise following chronic inflammation are usually squamous cell carcinomas.
At the time of diagnosis, approximately 70% of patients diagnosed with UC have tumours that are pathologically staged as pTa, pT1 or carcinoma in situ (CIS) i.e., non-muscle invasive (NMI) disease and these patients can have a good prognosis. When a patient's tumour is pathologically defined as ≥T1G3 UC, the patient is deemed to have a high risk of progression to a more life threatening disease. Muscle invasive UC (MI UC) encompasses all pathological stages≥pT2. The risk parameters that are currently used to tailor follow-up for patients diagnosed with UC, include pathological parameters i.e., grade, stage and associated CIS, together with resistance to Bacille Calmette-Guerin treatment. However, it is not always possible to correctly predict the outcome for patients. This is largely attributable to the molecular heterogeneity within tumours which means that a spectrum of outcomes, spanning from negligible risk to life threatening prognosis, exists within the same pathologically classified groups. For this reason, all patients with NMI disease have frequent surveillance cystoscopies and those with MI have radiological surveillance for lymph node recurrence or distant metastasis.
Cystoscopy is the gold standard for the detection and surveillance of NMI UC. However, this procedure is costly for health services and invasive for the patient. Furthermore, it requires a significant clinical input and has its own shortcomings. Cytology, another diagnostic test for urothelial cancer, detects the presence of malignant cells in urine. Although cytology has high specificity, it has insufficient sensitivity to stand alone as a diagnostic test for UC in patients presenting with haematuria. Despite their approval by the Food and Drug Administration (FDA), three diagnostic urothelial cancer biomarkers, Nuclear Matrix Protein 22, Bladder Tumour Antigen (BTA) and Fibrinogen Degradation Product, are not in use in routine practise as diagnostic biomarkers for UC because of their limited specificity. There is therefore a strong clinical need for tests which can at least stratify risk of UC, and if possible, be diagnostic in haematuric patients.
Researchers often combine multiple tests, genes or biomarkers. However, it is not possible to intuitively predict how multiple measurements, will collectively reflect the underlying biological heterogeneity in complex diseases, such as UC. Complex diseases consist of multiple components which interact to produce emergent properties that the individual components do not possess.
Smoking and occupational carcinogen exposure are risk factors in approximately 60% of UCs; other known risk factors include increased age, male gender, recurrent urinary infections and bladder stones. However, the factors which confound diagnosis of UC and the characteristics of incorrectly classified patients have not been systematically investigated. Identification of patient characteristics associated with misclassification or misdiagnosis can be useful because this information allows meaningful application of diagnostic classifiers for risk stratification.
Therefore, there is a need for new approaches to identifying factors that confound diagnosis of serious disease. Identification of such factors would enable clinicians to interpret risk classifiers alongside other clinical information at the time of triage, in order to make more accurate diagnoses. In the case of patients presenting with haematuria this would reduce the number of cystoscopies and enable priority diagnosis of aggressive UC and other serious diseases, resulting in improved patient outcomes at reduced costs.